tbuckley/cabot-search huggingface dataset:
Abstract 2405: Expression of the low affinity neurotrophin receptor (p75NTR) correlates with perineural invasion in adenoid cystic carcinoma of the lacrimal gland
Authors: Acadia H. Moeyersoms, Ryan A. Gallo, Madison Weiss, Michelle M. Maeng, David T. Tse, Daniel Pelaez
Journal: Cancer Research (2022)

Abstract Lacrimal gland adenoid cystic carcinoma (LGACC) is a rare but highly lethal indolent cancer originating in the cells of secretory glands, primarily of the head and neck. With the 10-year survival rate of 20%, the only life extending technique is to remove the eye and surrounding socket contents followed by extensive chemoradiation. Despite radical treatment, LGACC has a poorer prognosis than head and neck adenoid cystic carcinoma in part due to its propensity for perineural invasion (PNI) and intracranial spread. Analysis of LGACC tumors has revealed signatures enriched for pathways known to be involved in normal LG development, suggesting LGACC tumor cells re-engage or hijack developmental programs during its progression. This project sought to evaluate if developmental pathways involved in embryologic LG innervation were similarly recapitulated by LGACC tumors, and whether any of those markers could be correlated to perineural invasion phenotypes. We performed microarray analysis of embryonic and adult murine lacrimal glands and generated a differential expression signature associated with normal LG developmental pathways. Among other pathways, Notch and FGF signaling are significantly upregulated during LG organogenesis and our group and others have shown that activating mutations in these pathways are correlated with poor prognosis in LGACC. Interestingly, among the highest differentially expressed genes in the embryonic LG was the low-affinity nerve growth factor receptor (p75NTR). We thus subsequently evaluated the expression of p75NTR in LGACC tumors and its correlation to PNI. Our immunofluorescent imaging of histologically confirmed tumors with PNI demonstrated that p75NTR is highly correlated to cancer cells that have invaded the nerve. This correlation of p75NTR expression in nerve infiltrating LGACC cells can inform our investigation into the mechanisms for LGACC PNI and elucidate possible therapeutic targets to limit this aggressive manifestation in LGACC. Citation Format: Acadia H. Moeyersoms, Ryan A. Gallo, Madison Weiss, Michelle M. Maeng, David T. Tse, Daniel Pelaez. Expression of the low affinity neurotrophin receptor (p75NTR) correlates with perineural invasion in adenoid cystic carcinoma of the lacrimal gland [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2405.
Abstract 5308: Therapeutical antibody against CD25 mediating depletion of regulatory T cells without interruption of IL-2 signaling enhances antitumor immunity
Authors: Hao Peng, Shuangshuang Hu, Yuli Li, li Ding, Jinying Ning, Guojin Wu
Journal: Cancer Research (2022)

Abstract Regulatory T cell or suppressor T cell in tumor diminishes immune response to immunotherapy. CD25, the high-affinity receptor subunit for interleukin (IL)-2, is highly expressed on Treg and considered a selective target for Treg depletion. However, CD25 is also expressed on activated effector T cells (Teff), and antibodies against CD25 with blocking IL-2 signaling have limited antitumor activity. Here we developed a humanized antibody against CD25 (H3F1-4V2) without blocking IL-2 signaling. This antibody was derived from hybridoma of mice immunized with CD25-mFc. Two CD25 antibodies Daclizumab and RG6292 were applied as reference antibodies, and Daclizumab blocked IL-2 signaling, and RG6292 did not block IL-2 signaling. H3F1-4V2 had higher affinity to 293T cells overexpressing human CD25 than Daclizumab (EC50=0.4nM vs 0.45nM), with lower Kd (0.88nM vs 1.5nM). Because of high affinities, H3F1-4V2 and Daclizumab both efficiently depleted Treg from PBMC in vitro, while RG6292 depleted Treg with weaker ability because of low affinity to CD25. In the Teff, downstream signaling of IL-2 was analyzed, and Daclizumab significantly decreased pSTAT5, while RG6292 and H3F1-4V2 kept the pSTAT5 level intact. PBMC was cultured in the presence of CD25 antibodies, and Daclizumab inhibited T cell proliferation (ki67+%) and activation (Granzyme B+%), but not for RG6292 and H3F1-4V2. At last, these CD25 antibodies were tested in humanized mice whose CD25 was replaced with human CD25, and MC38 tumor cells were transplanted into these mice.H3F1-4V2 completely suppressed tumor growth, while RG6292 also suppressed tumor growth with weaker efficiency and Daclizumab had little effect on tumor growth. These results suggested H3F1-4V2 was the best candidate targeting CD25 for cancer therapy. Citation Format: Hao Peng, Shuangshuang Hu, Yuli Li, li Ding, Jinying Ning, Guojin Wu. Therapeutical antibody against CD25 mediating depletion of regulatory T cells without interruption of IL-2 signaling enhances antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5308.
Abstract 2215: Cancer awareness, tobacco use and cessation among Malayali tribes, Yelagiri Hills, Tamil Nadu, India
Authors: Delfin Lovelina Francis
Journal: Cancer Research (2022)

Abstract BACKGROUND: Health is a state of complete wellbeing free from any discomfort and pain. Despite remarkable world-wide progress in the field of diagnostic, curative and preventive medicine, still there are large populations of people living in isolation in natural and unpolluted surroundings far away from civilization, maintaining their traditional values, customs, beliefs and myths. India has the second largest tribal population of the world next to the African countries. The present study was conducted to assess the cancer awareness, tobacco use, and its effect on health among Malayali tribes, Yelagiri Hills, Tamil Nadu, India. METHODOLOGY: After a study among this population of 660 in 2010, an extended research was carried out in 2018 among 2185 participants. The inhabitants of the 14 villages of the Yelagiri hills, who were willing to participate in the study were included. Data was collected from a cross-sectional survey, using a Survey Proforma, clinical examination and a pre-tested questionnaire which included Demographic data, tobacco habits. A brief tobacco cessation counseling was given to all the users. SPSS version 21 was used for statistical analysis. RESULTS: Results showed that among 2185 study population, 47% had no formal education. Of those who had the habit of smoking, 29% smoked beedi, 31% smoked cigarette, 39% chewed raw tobacco, 33% chewed Hans and 12% had a combination of smoking and smokeless tobacco usage. Prevalence of oral mucosal lesions 47% and 7% oral cancer in the study population was due to tobacco usage and lack of awareness regarding the deleterious effects of the products used. CONCLUSION: From the results of this study it may be concluded that the Malayali tribes were characterized by a lack of awareness about oral health, deep rooted dental beliefs, high prevalence of tobacco use and limited access to health services. Citation Format: Delfin Lovelina Francis. Cancer awareness, tobacco use and cessation among Malayali tribes, Yelagiri Hills, Tamil Nadu, India [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2215.
Abstract 5739: Genetic characteristics of the early stage Chinese NSCLC patients
Authors: Naiquan Mao, Weishen Yao, Liufu Su, Xiaochun Huang, mengli Huang
Journal: Cancer Research (2022)

Abstract Background: Lung Cancer, predominantly non-small-cell lung cancer (NSCLC), is the leading cause of cancer-related death in China. Although precision therapies for patients with advanced or metastatic NSCLC have developed over the past two decades, the 5-year survival rate remains low at 0%-26%. Thus, recurrence monitoring and treatment at an early stage are of great significance for improving survival benefits. Here, we explored the genetic characteristics of early stage NSCLC patients to provide additional values to predict recurrence risk and treatment strategies. Methods: Tumor or plasma samples were collected from 146 Chinese NSCLC patients in stage I-III (127 LUAD, 5 LUSC, 2 LUASC, 12 unknown pathology). 733 cancer-related genes were sequenced on NGS platform for variants analysis. Tumor mutation burden (TMB) was defined by all somatic mutation counts in coding region per megabase. Immunohistochemistry (IHC) was performed using antibodies (clone 22C3 or SP263) to analyze PD-L1 expression. PD-L1 positivity was defined as TPS ≥1%. Online databases, such as cBioPortal, TIMER2.0 and Kaplan-Meier Plotter, were also used for analysis. Statistical analysis was performed using the R Software (v 4.0.5). Results: Of 146 NSCLC patients, commonly mutated genes were detected, including EGFR (68%), TP53 (40%), KMT2D (10%), MSH3 (9%), RBM10 (9%), ZFHX3 (9%). Six pathogenic or likely pathogenic fusion variants harbored in common driver genes like EGFR, ALK and ROS1 were identified for the first time. EGFR was more frequently mutated in female patients (P &amp;lt; 0.01), while CDH10 mutations occurred more often in male patients (P &amp;lt; 0.05). Correlation analysis showed RBM10, ZFHX3 and CTNNB1 mutations were respectively co-occurrent with CARD11, ARHGAP5 and APC, reflecting the distinct profile of our cohort when compared to cBioPortal. Patients with TP53mut, MSH3mut or LRP1Bmut had significantly higher TMB (P &amp;lt; 0.05). Compared to PD-L1- group, TP53, TIMELESS, FBXW7 were remarkably mutated in PD-L1+ group. In LUAD, SPTA1mut and TIMELESSmut were noticeably related to CD8+T and B cell infiltration, while FBXW7mut and ZFHX3mut with more M1 macrophages infiltration. Prognostic analysis showed that LUAD patients harboring MSH3mut (P &amp;lt; 0.001) and SPENmut (P = 0.0005) at stage II exhibited significantly shorter RFS. Moreover, we found that cases carried somatic mutations in TP53 signaling pathway had more lymph node metastasis. Conclusion: These findings expanded our understanding of the early stage Chinese NSCLC, hopefully providing valuable guidance for recurrence risk prediction and treatment strategies. Citation Format: Naiquan Mao, Weishen Yao, Liufu Su, Xiaochun Huang, mengli Huang. Genetic characteristics of the early stage Chinese NSCLC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5739.
PI3King the Environment for Growth: PI3K Activation Drives Transcriptome Changes That Support Oncogenic Growth
Authors: Sally E. Claridge, Benjamin D. Hopkins
Journal: Cancer Research (2022)

Abstract PI3K signaling plays an integral role in cells, coordinating the necessary alterations in cellular metabolism and programs to support survival and proliferation. In the first genome-wide analysis of alternative splicing in PIK3CA-mutant breast cancer, Ladewig and colleagues show that activating mutations in PIK3CA alter the use of known exons and splice junctions, leading to changes in gene expression and transcription factor activity that promote an oncogenic phenotype. Their work reveals a novel mechanism underlying the functional impact of PI3K signal activation in the context of breast cancer, where PIK3CA mutations are common and PI3K inhibitors are part of the standard of care. Their studies uncover a feedforward mechanism by which PI3K signaling enables a shift in the spectrum of translated splice variants as another method through which the PI3K pathway has evolved to regulate its own activity, thereby modifying the cellular response to upstream activation based on the signaling that has come before. These findings have profound implications for understanding the evolution of the PI3K pathway and the rewiring of cells in response to prolonged or repeated signal activation. See related article by Ladewig et al., p. 2269
Abstract 796: Dual inhibition of NHEJ and MMEJ induces synthetic lethality in TP53 mutant cancers
Authors: Jeffrey Patterson-Fortin, Arindam Bose, Wei-Chih Tsai, Carter Grochala, Huy Nguyen, Jia Zhou, Kalindi Parmar, Jean-Bernard Lazaro, Joyce Liu, Kelsey McQueen, Geoffrey I. Shapiro, David Kozono, Alan D. D'Andrea
Journal: Cancer Research (2022)

Abstract DNA repair pathway inhibitors are a new class of anti-cancer drugs that are advancing in clinical trials. While inhibitors of targets in the Non-Homologous End Joining (NHEJ) DNA repair pathway, such as DNA-dependent protein kinase (DNA-PK), are available for clinical use, it remains unclear which cancers are vulnerable to these agents. In a genome-wide CRISPR knockout screen with the DNA-PK inhibitor M3814, we identify loss of POLQ, encoding polymerase theta, and other genes in the microhomology-mediated end-joining (MMEJ) pathway as key predictors of sensitivity to DNA-PK inhibition, whereas loss of TP53 conferred resistance to DNA-PK inhibition. Inhibition of DNA-PK led to increased DNA double strand break end-resection, increased expression of polymerase theta, and activation of MMEJ repair. Combined DNA-PK inhibition by M3814 and polymerase theta inhibition by novobiocin resulted in synthetic lethality mediated by the accumulation of resected DNA and apoptosis. Significantly, this drug combination efficiently killed TP53-deficient human patient-derived xenografts and the corresponding tumor organoids. Taken together, our results provide a rationale for the combination of an inhibitor of DNA-PK mediated NHEJ and an inhibitor of polymerase theta mediated MMEJ in an anti-cancer trial. If DNA-PK is inhibited, cancers develop a hyper-dependence on MMEJ and an upregulation of DNA double strand break end resection and polymerase theta expression. Similarly, P53-deficiency which confers resistance to DNA-PK inhibition, also leads to a hyper-dependence on MMEJ and an upregulation of polymerase theta expression. Thus, a combination of DNA-PK and polymerase theta inhibitors may provide a precision treatment strategy for TP53-mutant solid tumors, known to account for 50% of newly diagnosed cancers. Citation Format: Jeffrey Patterson-Fortin, Arindam Bose, Wei-Chih Tsai, Carter Grochala, Huy Nguyen, Jia Zhou, Kalindi Parmar, Jean-Bernard Lazaro, Joyce Liu, Kelsey McQueen, Geoffrey I. Shapiro, David Kozono, Alan D. D'Andrea. Dual inhibition of NHEJ and MMEJ induces synthetic lethality in TP53 mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 796.
Extreme Heat Exposure: Access and Barriers to Cooling Centers — Maricopa and Yuma Counties, Arizona, 2010–2020
Authors: Evan Mallen, Matthew Roach, Laura Fox, Elizabeth Gillespie, Lance Watkins, David M. Hondula, Ambarish Vaidyanathan, Arie Manangan, Ayana N. Perkins, Paul J. Schramm
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Extreme heat exposure increases the risk for heat-related illnesses (HRIs) and deaths, and comprehensive strategies to prevent HRIs are increasingly important in a warming climate (1). An estimated 702 HRI-associated deaths and 67,512 HRI-associated emergency department visits occur in the United States each year (2,3). In 2020, Phoenix and Yuma, Arizona, experienced a record 145 and 148 days, respectively, of temperatures >100°F (37.8°C), and a record 522 heat-related deaths occurred in the state. HRIs are preventable through individual and community-based strategies*,†; cooling centers,§ typically air-conditioned or cooled buildings designated as sites to provide respite and safety during extreme heat, have been established in Maricopa and Yuma counties to reduce HRIs among at-risk populations, such as older adults. This analysis examined trends in HRIs by age during 2010-2020 for Maricopa and Yuma counties and data from a survey of older adults related to cooling center availability and use in Yuma County during 2018-2019. Data from CDC's Social Vulnerability Index (SVI) were also used to overlay cooling center locations with SVI scores. During 2010-2020, heat days, defined as days with an excessive heat warning issued by the National Weather Service Phoenix Office,¶ for any part of Maricopa and Yuma counties (4), increased in both Maricopa County (1.18 days per year) and Yuma County (1.71 days per year) on average. Adults aged ≥65 years had higher rates of HRI hospitalization compared with those aged <65 years. In a survey of 39 adults aged ≥65 years in Yuma County, 44% reported recent HRI symptoms, and 18% reported electricity cost always or sometimes constrained their use of air conditioning. Barriers to cooling center access among older adults include awareness of location and transportation. Collaboration among diverse community sectors and health profession education programs is important to better prepare for rising heat exposure and HRIs. States and communities can implement adaptation and evaluation strategies to mitigate and assess heat risk, such as the use of cooling centers to protect communities disproportionately affected by HRI during periods of high temperatures.
The efficacy and safety of anti–PD-1 antibody toripalimab combined with surufatinib in neoadjuvant treatment of locally advanced thyroid cancer: A phase II study.
Authors: Jiaying Chen, Qinghai Ji, Yu Wang, Naisi Huang, Jiaqian Hu, Wenjun Wei, Caiping Huang, Qiang Shen, Duanshu Li
Journal: Journal of Clinical Oncology (2022)

6084 Background: Surgery is the primary treatment for locally advanced thyroid cancer. However, some locally advanced patients are not candidates for R0/1 resection. There is limited evidence of neoadjuvant treatment in locally advanced thyroid cancer. Surufatinib targets multiple kinases (VEGFR1-3, FGFR1 and CSF-1R) involved in tumor angiogenesis and tumor immune evasion. It is efficient, tolerable and safe for patients with radioiodine-refractory differentiated thyroid cancer to receive surufatinib. In addition, surufatinib plus toripalimab (an anti-PD-1 antibody) showed encouraging antitumor activity and an acceptable safety profile in advanced solid tumors. This study aimed to evaluate the efficacy and safety of surufatinib plus toripalimab in locally advanced thyroid cancer in the neoadjuvant setting. Methods: In this single-arm phase II study, patients with pathologically confirmed diagnosis of unresectable or borderline resectable differentiated thyroid cancer were eligible and received a combination of 250 mg surufatinib (oral, qd) with 240 mg toripalimab (IV, q3w). Treatment was continued until satisfied for curative surgery, disease progression, withdrawal of consent, unacceptable toxicity or investigator decision. Primary endpoint was objective response rate (ORR) by RECIST 1.1. Secondary endpoints included R0/1 resection rate, disease control rate (DCR), time to remission (TTR), adverse events (AEs), etc. Results: This study is ongoing. 10/10 patients were enrolled. 6 patients received ≥4 cycles of surufatinib plus toripalimab treatment and were also evaluated for efficacy. The ORR was 66.7% with 4 partial response (PR) and 2 stable disease (SD). 4 PR and 1 SD patients received R0 resections after neoadjuvant treatment. The safety was consistent with previously reported. No grade ≥3 AEs were observed. Specific AEs data are still being counted. Conclusions: Surufatinib in combination with toripalimab as neoadjuvant therapy for locally advanced thyroid cancer was feasible and majority of patients achieved R0 resection. AEs were mainly grade 1-2, and this combination was well-tolerated. The combination of these two agents should be further investigated for neoadjuvant treatment of locally advanced thyroid cancer based on good results. Clinical trial information: NCT04524884.
Abstract 6379: Dipeptidyl peptidase-4 inhibitor impairs the outcomes of patients with type 2 diabetes mellitus after curative resection for colorectal cancer
Authors: Akira Saito, Hideyuki Ohzawa, Yuki Kaneko, Kohei Tamura, Yurie Futoh, Kazuya Takahashi, Yuki Kimura, Mineyuki Tojo, Rie Kawashima, Hideyo Miyato, Naohiro Sata, Joji Kitayama
Journal: Cancer Research (2022)

Abstract Background: Type2 diabetes mellitus(T2DM) is a risk factor for cancer. Recent studies have shown that DPP-4 inhibitor(DPP-4i) can either promote or suppress cancer progression. However, the detailed mechanisms remain unknown. Here, in this study, we investigated the effect of DPP-4i on tumor microenvironment and its effect on the prognosis of cancer patients. Method: We retrospectively examined the outcome of colorectal cancer (CRC) patients with T2DM who received curative surgery in Jichi Medical University Hospital and asked the impact of DPP-4i intake on their outcome. In addition, we performed immunohistochemistry to examine the phenotypes of TIL, TAM and epithelial-mesenchymal transition (EMT) of cancer cells in surgically removed CRC tissues in 40 CRC patients who had taken DPP-4i and propensity score-matched 40 patients who had not. Results: A total of 1696 patients underwent curative colectomy from April 2010 to March 2020. Among them, 260 patients had T2DM at the time of surgery, and 135 patients had been treated with drugs including DPP-4i. The postoperative disease-free survival rate (DFS) was significantly worse in the DPP-4i intake group compared with non-intake group (5 year DFS 18.5% vs 5.4%, HR=2.0, p&amp;lt;0.05). The number of Zeb1-positive tumor cells significantly increased in DPP-4i intake group. (Median(M)=29.0 (0-189)/mm2 vs 9.0 (0-71)/mm2, p&amp;lt;0.01). The number of CD3 (+) TIL in DPP-4i intake group was Median(M)=277.4(min 121.6-max 523.2)/mm2 which was significantly lower than those in non-intake group (M= 319.6, min 493.0-max 823.6/mm2). CD8(+) TIL in DPP-4i intake was reduced more significantly than in non-intake group (M=187.6, min 67.8-max 347.4/mm2 vs M=336.8, min 200.2-max 588.4/mm2, p&amp;lt;0.05) with less CD8/CD3 ratio (61.2% vs 67.1%, p&amp;lt;0.05). On the other hand, the density of CD68(+)CD163(+) TAM was significantly higher(M=202.6, min 122.8-max 257.0/mm2 vs M=126.6, min 94.8-max 247.6/mm2, p&amp;lt;0.05) in DPP-4i intake group. Conclusion: DPP-4i increases the number of M2-type TAM while decreases the number of effector TIL and promote EMT of cancer cells in tumor microenvironment, which might lead to the poor outcome of the patients with CRC. Citation Format: Akira Saito, Hideyuki Ohzawa, Yuki Kaneko, Kohei Tamura, Yurie Futoh, Kazuya Takahashi, Yuki Kimura, Mineyuki Tojo, Rie Kawashima, Hideyo Miyato, Naohiro Sata, Joji Kitayama. Dipeptidyl peptidase-4 inhibitor impairs the outcomes of patients with type 2 diabetes mellitus after curative resection for colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6379.